The development of APP transgenic (APP/Tg) mouse models of Alzheimer's disease (AD) provides a valuable experimental system in which to test hypotheses on the mechanisms underlying the onset and progression of AD, as well as potential therapeutic approaches. Initial reports by Schenk et al., together with recent publications, have demonstrated that immunization of APP/Tg mice with fibrillar Abeta1-42 (Abeta42)peptide blocked the deposition and initiated the removal of existing Abeta deposits from the brain. In addition, it was established that anti-Abeta antibodies could protect mice from Alzheimer's disease-like memory loss. However, a number of questions remain unanswered regarding the role of cellular immune responses to Abeta, Abeta clearance mechanisms, the potential for an autoimmune response, and problems relating to the expected variability of immune responses resulting from the highly polymorphic nature of the MHC. The cost, safety and efficacy of immunization with Abeta peptide are all critical factors that must be carefully evaluated in order to develop a successful vaccine. The ideal Abeta vaccine should target the immune response to immunogenic epitopes of Abeta that are critical for clearance, and not "non-functional" antibodies that may contribute to unwanted side effects. Thus, the goals of the current proposal are: (i) to examine extensively the primary (IgM) and secondary (IgGl, IgG2a) humoral and cellular (T-helper 1, T-helper 2, and CTL) immune responses to Abeta42 in mice of different haplotypes, including APP/Tg F1 animals; (ii) to analyze the magnitude of humoral and cellular immune responses in high and low responders, as well as in APP/Tg mice, using multiple vaccine approaches (peptides, DNA, phage displaying peptide, or a combination of these immunogens); (iii) to investigate the affect of aging on the immune response to the best vaccination regimen in APP/Tg mice; (iv) to test the efficacy of this immunization on behavioral impairment of APP/Tg mice and analyze Alzheimer's disease-like pathology in these animals. Therefore, both prophylactic and therapeutic vaccination will be tested.